Compounds of the Formulae I and II: ##STR1## are inhibitors of leukotriene biosynthesis as evidenced by their activity in vitro in the polymorphonuclear leukocyte assay. These compounds inhibit the mammalian 5-lipoxygenase enzyme, thus preventing the metabolism of arachidonic acid to the leukotrienes. Inhibition of 5-lipoxygenase enzyme, therefore diminishes the adverse effects of leukotrienes. The leukotrienes play an important role in inducing allergic reactions, such as: asthma, bronchitis and rhinitis.
There are two groups of leukotrienes derived from a common unstable precursor, Leukotriene A.sub.4. The first of these are the peptido-lipid leukotrienes, the most important being leukotrienes C.sub.4 and D.sub.4. These compounds collectively account for the biologically active materials known as the slow reacting substances of anaphylaxis. They are potent smooth muscle contracting agents, particularly on respiratory smooth muscle, but also on other tissues. In addition they promote mucous production, modulate vascular permeability changes and are potent inflammatory agents in human skin.
The more important compound in the second group of leukotrienes is Leukotriene B.sub.4, a dihydroxy fatty acid derived from Leukotriene A.sub.4. This compound is a potent chemotactic agent for neutrophils and eosinophils. When injected in vivo, in addition to promoting the accumulation of leukocytes, Leukotriene B.sub.4 is also a potent hyperanalgesic agent and can modulate vascular permeability changes through a neutrophil dependent mechanism. Both groups of leukotrienes are formed following oxygenation of arachidonic acid through the action of the 5-lipoxygenase enzyme. See D. Bailey and F. Casey, Ann. Rpts. Med. Chem. 17:203 (1983).
Leukotrienes can also mediate other disease states and these include: psoriasis, atopic dermatitis, gouty arthritis and gall bladder spasms. They also may play a role in cardiovascular disease because Leukotrienes C.sub.4 and D.sub.4 act as coronary and cerebral arterial vasoconstrictors and these compounds may also have negative ionotropic effects on the myocardium. In addition, the leukotrienes are important mediators of inflammatory diseases through their ability to modulate leukocyte and lymphocyte function. See B. Samuelsson, Science 220:568 (1983).
Recent studies demonstrated that macrophages participate in the development and progression of chronic inflammatory diseases, such as, rheumatoid arthritis. During the progression of inflammatory conditions, there is generally an appearance and/or presence of macrophages and polymorphonuclear leukocytes. Macrophages are known to secrete various products in response to inflammatory stimuli. These oxygenated arachidonic acid products, also known as leukotrienes, have been identified as the critical mediators of various acute inflammatory conditions.
The pharmacological agents such as 5-lipoxygenase inhibitors, which are capable of inhibiting the formation of leukotrienes or agents capable of inhibiting the release of leukotrienes can there by interfere with the function of macrophages or PMN leukocytes. These may also be effective agents in the treatment of a variety of inflammatory conditions, such as: pain, fever, rheumatoid arthritis, emphysema, asthma, allergic disorder, bronchial inflammation, osteoarthritis, acute respiratory distress syndrome, inflammatory bowel disease, spondy citis, lupus, gout, psoriasis, and cardiovascular disorders.
The hexahydrodibenzofuran structural framework has been shown to have anti-inflammatory and analgesic activity. The following patents described the wide variety of uses found for the tetra and hexahydrodibenzofuran structural type.
American Cyanamid has three U.S. Pat. Nos. (3,646,060-S, 3,741,992-S and 3,741,991-S) describing the utility of 4a,9b-dihydro-8,9b-dimethyldibenzofurans as analgesic agents. Ciba-Giegy AG has disclosed in CH 542,838-R, CH-543,500 7- or 8-substituted-alkanoic acid-1,2,3,4-tetrahydrodibenzofurans and thiophenes derivatives as useful hypolipaemic agents. The third utility shown for the dibenzofuran structure type has been demonstrated by Hoffmann-LaRoche in U.S. Pat. Nos. 3,803,180 and 3,931,288 as anti-inflammatory and antirheumatic agents. Parke-Davis & Co. (U.S. Pat. No. 3,159,677) has claimed the 7- and/or 8-substituted-4a-amino-1,2,3,4,9b-tetrahydrodibenzofuran serve as orally and parenterally active CNS-depressants. Merck and Co. has shown in U.S. Pat. No. 4,769,370A that 1,2-dihalo or dialkyl-8-oxo-5a-substituted-tetrahydrodibenzofuran-3-ylalkanoic acids and alkanimidamides are useful for the treatment of injury to the brain or spinal cord. Riom Labs has discovered the 4a-4-phenylhydroxyethylpiperazinylmethyl-1,2,3,4,4a,9b-hexahydrodibenzofur an-4-one or 4-ol derivatives described in EP 67-769 are antibronchoconstrictors. Nippon Soda in J6 0016-980A has shown 1,2,3,4,4a,9b-hexahydro-9-{2-hydroxy-3-(1-methylethylamino)propoxy}dibenzo furan derivatives to have beta-blocking activity. Hoechst Roussel Pharmaceutical in U.S. Pat. No. 3,646,060-S and Upjohn Co. in Neth. 6,415,270 describe the use of 1,2,3,4,4a,9b-hexahydro-4a-aminoalkyldibenzofurans as analgesics, anticonvulsants and antidepressants.
The structures described within this application have a novel substitution pattern which is felt to enhance the binding to the 5-lipoxygenase enzyme and in turn better inhibit the production of leukotrienes, thereby enhance the anti-inflammatory activity.